PB1760: AZACITIDINE AS TREATMENT OF KMT2A INFANT ACUTE LYMPHOBLASTIC LEUKEMIA: SINGLE CENTER EXPERIENCE
Authors: G. Giagnuolo, A. De Matteo, P. Stellato, F. Petruzziello, R. Cuccurullo, G. Beneduce, F. Cacace, F. P. Tambaro, R. Parasole, G. Menna
Journal: HemaSphere (2022)

Background: KMT2A rearranged (r) infant acute lymphoblastic leukemia (ALL) is characterized by a very poor prognosis, particularly after relapse. Intensive chemotherapy does not improve outcome and novel therapies are under investigation for this dismal disease. Recent studies reported an hypermethylated DNA profile in KMT2Ar ALL, leading to repression and silencing of tumor suppressor genes. Hypomethylating agents (HMA) have been hypothesized to exert an antileukemic activity restoring normal gene expression. Aims: Here we report the off-label administration of Azacitidine (AZA) in two little patients aged 1 month old and 26 days old respectively, diagnosed with KMT2Ar infant ALL. Methods: Both patients were treated according to the high risk arm of the AIEOP-BFM ALL 2017 protocol as front-line therapy. AZA was administered every 21 days (d) for 4 cycles (cy), with the following schedule: 55 mg/m2 for 5 d, 55 mg/m2 for 7 d, 75 mg/m2 for 5 d, 75 mg/m2 for 7 d, respectively; prednisone 1 mg/m2 was associated to each cycle. Results: Patient 1 was diagnosed with infant B ALL t(11;19)/KMT2A-MLLT1r, high-risk (HR) for age, hyperleucocytosis and KMT2Ar. At the end of induction (EOI) he was in hematologic remission with molecular minimal residual disease (MRD) and t(11;19) still detectable. The child received consolidation chemotherapy followed by 2 cy of bispecific CD3-CD19 antibody (ab) Blinatumomab and underwent allogeneic hematopoietic stem cell transplant (HSCT) from matched unrelated donor (MUD) with detectable MRD. Two months after transplant patient relapsed with 68% CD19 CD22 negative blasts in bone marrow. Due to early relapse and no target therapy available, AZA was administered. Grade 4 cytopenia and pneumonia were main adverse events. Patient achieved MRD complete remission (CR) and underwent to haploidentical HSCT from mother, followed by 3 courses of 40 mg/m2 AZA maintenance for 5 d, every 21 d. Patient is alive, in MRD negative CR3, 3 months after SCT. Patient 2 was diagnosed with infant B ALL t(4;11)/KMT2A-AFF1, HR for age, hyperleucocytosis and KMT2Ar. At the EOI bone marrow showed blasts 25% detected by flow cytometry. Patient received one courses of chemotherapy according to the HR protocol, followed by 2 cy of Blinatumomab. The child achieved MRD negative CR and underwent HSCT from MUD. Thirty two days after HSCT, patient relapsed with 60% BM blasts detected by flow cytometry. Due to early relapse after HSCT, he received 2 cy of anti-CD22 ab Inotuzumab, achieving CR without platelet recovery (CRi). Nevertheless, t(4;11) was positive again at the end of the 2nd cy. Patient then received AZA as 3th-line therapy achieving CRi after 2nd cy. However, due to severe cytopenia and gastrointestinal toxicity, patient received 3 out of 5 days treatment of the 3th cy and the 4th cy was delayed. Patient relapsed after the 4thcourse. Summary/Conclusion: In our experience, single agent AZA alone was effective and well tolerated in heavily pretreated patients. To our knowledge, single agent HMA in KMT2Ar ALL has been reported only in one patient. Preclinical studies have revealed heterogeneous results when HMA are combined with cytotoxic drugs; results of two pilot trials of AZA combined with chemotherapy are still ongoing. Further clinical trials could clarify the optimal schedule, timings and dosage of HMA.